In patients with non-small cell lung cancer (NSCLC), tumor stage is the strongest determinant of prognosis. Stratification of patients into stages facilitates individual treatment decisions based on the survival statistics of a population. Within these staged populations however, subsets of patients with apparent early disease will still suffer cancer recurrence. This is due to the inability of current staging methods to detect small numbers of disseminated tumor cells (micrometastases) in these patients. Reverse transcription-PCR (RT-PCR) has been shown to detect the presence of micrometastases in histologically negative specimens, and these findings correlate with poor outcome. Unfortunately, routine clinical application of this technique has been limited by """"""""false positive"""""""" results in control tissues, a low specificity for predicting disease recurrence, and the lack of simple, standardized assays for multi-center trials. We address these issues in this proposal. We have recently shown that quantitative RT-PCR (QRT-PCR) can discriminate between true and false positives, and that this results in an improved ability to predict recurrence. Furthermore, in our study of 30 histologically node negative esophageal cancer patients, a positive QRT-PCR result was the strongest, independent risk factor for recurrence. Thus, in Specific Aims 1 and 2 of this proposal, we will use QRT-PCR for carcinoembryonic antigen (CEA) and cytokeratin 19 (CK 19) to detect micrometastases in the lymph nodes, blood and bone marrow of NSCLC patients. Recurrence and survival data will enable us to determine the prognostic value of QRT-PCR for detecting both lymphatic and hematogenous tumor spread. Our goal is to improve the accuracy of NSCLC staging so that prognosis and treatment options are more closely correlated with individual patient outcomes.
In Specific Aim 3 we will work with an industry collaborator to develop a cartridge based, automated assay that can be used in multi-center trials. In addition, this assay uses a rapid QRT-PCR method that can be completed in less than twenty minutes. This assay could therefore be used at the time of surgical staging, to direct the use of neoadjuvant therapies. Preliminary data show that our 'intraoperative QRT-PCR' is more sensitive than intraoperative frozen section histology; it may also detect micrometastases missed by final pathologic examination. Thus, molecular information regarding micrometastases could, for the first time, be made available intraoperatively to the surgeon.
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| Xi, Liqiang; Feber, Andrew; Gupta, Vanita et al. (2008) Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer. Nucleic Acids Res 36:6535-47 |
| Xi, Liqiang; Coello, Michael C; Litle, Virginia R et al. (2006) A combination of molecular markers accurately detects lymph node metastasis in non-small cell lung cancer patients. Clin Cancer Res 12:2484-91 |
| Xi, Liqiang; Lyons-Weiler, James; Coello, Michael C et al. (2005) Prediction of lymph node metastasis by analysis of gene expression profiles in primary lung adenocarcinomas. Clin Cancer Res 11:4128-35 |
